1. Field of the Invention
The present invention relates generally to the medical and industrial fields. More particularly, it concerns a gallium-containing composition to prevent or inhibit biofilm growth formation and infections arising therefrom.
2. Description of Related Art
Bacterial contamination of medical devices are commonly caused by biofilm formation which leads to infections such as nosocomial infections. Nosocomial pneumonia is the second most common nosocomial infection, and is associated with the highest attributable mortality and morbidity. For example, the risk of nosocomial pneumonia has dramatically increased over the years from the use of mechanical ventilation equipment (Official Statement, American Thoracic Society). Nosocomial infections, especially those involving the bloodstream or lung often cause death.
Population-based surveillance studies of nosocomial infections in U.S. hospitals indicate a 5% attack rate or incidence of 5 infections per 1,000 patient-days (Wenzel et al., 2001). The Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) surveillance system of nosocomial bloodstream infections in U.S. hospitals identified a crude mortality rate of 27%, with great variation by pathogen. Estimates of nosocomial bloodstream infections from the SCOPE database indicate that 70% occur in patients with central venous catheters (Wenzel et al., 1999). SCOPE has identified that 49% of all nosocomial bloodstream infections occur in intensive-care units where patients often have weakened immune systems and are frequently on ventilators and/or catheters on which bacteria often form biofilms.
Nosocomial pneumonia is also commonly caused by endotracheal tubes which are common vehicles for bacterial colonization/contamination leading to biofilm growth formation. The endotracheal tube connects the oropharyngeal environment with the sterile bronchoalveolar space, significantly increasing the risk of nosocomial pneumonia. Formation of biofilms within endotracheal tubes plays a role in the initiation of ventilator-associated pneumonia and may select for antibiotic resistance among bacterial species causing such infections (Sottile et al., 1986; Inglis et al., 1989; Adair et al., 1993; Koerner et al., 1998; Gorman et al., 2001; Adair et al., 1999).
A primary contributor to nosocomial bloodstream infections are vascular catheters. It is estimated that around 400,000 vascular catheter-related bloodstream infections (CRBSI) occur annually in the United States (Raad, 1998). Another frequent causes of nosocomial infections are urinary tract infections (UTI), which contribute to 34% of all nosocomial infections (Klempner et al., 1998). Nosocomial UTI are usually associated with contamination of urinary catheters.
In addition, nosocomial infections due to biofilm growth formation are common complications of surgical procedures, particularly in cancer and immunocompromised patients with devitalized tissue and decreased immunity. Surgical wound infections contribute to 17% of all nosocomial infections (Platt and Bucknall, 1988). Many surgical wound infections are associated with the bacterial contamination of sutures.
Antibiotics and antiseptics have been used to coat/impregnate devices on which bacteria may grow and form biofilms, leading to infection such as nosocomial infections. However, although these infections can be controlled for many years by antibiotics, ultimately the bacteria (e.g., P. aeruginosa) form a biofilm that is resistant to antibiotic treatment therefore rendering these agents therapeutically ineffective. The durability of existing antiseptics in controlling biofilm formation has also been limited.
Several studies have examined the effect of various types of antimicrobial treatment in controlling biofilm formation on devices. For example, the use of chlorohexidine/silver sulfadiazine in impregnating the surface of vascular catheters resulted in limited activity against gram-negative bacilli, such as Pseudomonas. Catheters impregnated with minocycline and rifampin were somewhat effective in preventing bacterial colonization (Darouiche et al., 1999). Anwar et al. (1992) showed that treatment with levels of tobramycin far in excess of the MIC reduced biofilm cell counts for P. aeruginosa by approximately 2 logs, while the same dosage provided a >8-log decrease in planktonic cells of this organism. Addition of sodium metabisulfite to a dextrose-heparin flush eliminated microbial colonization of atrial catheters (Freeman and Gould (1985). Catheters coated with a cationic surfactant (tridodecylmethylammonium chloride), which was in turn used to bond cephalosporin to the surface, were found less likely to become contaminated and develop biofilms than were untreated catheters (Kamal et al., 1991). Flowers et al. (1989) found that an attachable subcutaneous cuff containing silver ions inserted after local application of polyantibiotic ointment conferred a protective effect on catheters, resulting in lower rates of contamination. Maki (1994) suggested several ways to control biofilms on central venous catheters, including using aseptic technique during implantation, using topical antibiotics, minimizing the duration of catheterization, using an in-line filter for intravenous fluids, creating a mechanical barrier to prevent influx of organisms by attaching the catheter to a surgically implanted cuff, coating the inner lumen of the catheter with an antimicrobial agent, and removing the contaminated device.
Antiseptics used in industrial applications have also failed to prevent biofilm growth formation of bacterial organisms. For example, industrial water contamination and public health issues due to an outbreak of P. aeruginosa peritonitis was traced back to contaminated poloxamer-iodine solution, a disinfectant used to treat the peritoneal catheters. P. aeruginosa was found to contaminate distribution pipes and water filters used in plants that manufacture iodine solutions. Once the organism had matured into a biofilm, it became resistant to the biocidal activity of the iodophor solution. Hence, biofilm growth formation causes mechanical problems in industrial settings, which in some instances may lead to infections in humans.
Other methods of inhibiting biofilm formation in medical and industrial settings have previously been developed using metal chelators (U.S. Patent Application Ser. No. 60/373,461). These methods have disclosed the use of small molecule chelators, i.e., EDTA, EGTA, deferoxamine, detheylenetriamine penta-acetic acid and etidronate for the inhibition of biofilm. U.S. Pat. No. 6,267,979 discloses the use of metal chelators in combination with antifungal or antibiotic compositions for the prevention of biofouling in water treatment, pulp and paper manufacturing, and oil field water flooding. U.S. Pat. No. 6,086,921 discloses the use of thiol containing compounds in combination with heavy metals as biocides; and U.S. Pat. No. 5,688,516 discloses the use of non-glycopeptide antimicrobial agents in combination with divalent metal chelating agents for use in the treatment and preparation of medical indwelling devices.
Although the current methods used to control biofilm growth formation have been somewhat effective, biofilm growth formation continues to be problematic in a variety of setting such as medical and industrial environments. Therefore, better means of targeting biofilm growth formation are needed in the art.